The habit-forming effects of several addictive drugs have been linked to their ability to elevate levels of the neurotransmitter dopamine in certain brain regions. It is important to determine what other factors influence the dopamine system. We are currently studying the effects of leptin, a blood-borne hormone that affects reward function and the dopamine system. In order to identify neurotransmitter fluctuations that accompany drug-seeking behavior or that cause or are caused by fluctuations of dopamine, microdialysis samples are taken from various brain regions in animals trained to lever-press for intravenous drug injections. The results of these studies are integrated to identify the neuronal circuitry of addiction and drug-seeking. Our most recent finding is that regular self-administration of intravenous cocaine in rats causes depressions in circulating leptin levels and decreased leptin signaling in the dopamine system. Leptin levels are not only depressed by cocaine intake; they are depressed in anticipation of regular cocaine intake. We further find that leptin normally antagonizes the rewarding effects of cocaine and cocaine-associated stimuli; thus cocaine inhibits its own inhibitor. Because leptin modulates the effectiveness of cocaine and cocaine-associated cues we are assessing the leptin system as a potential target for pharmacotherapy for cocaine addiction. We have also found that cocaine and cocaine expectancy alters growth hormone, ghrelin, insulin, corticosterone, gastric inhibitory polypeptide, glucagon-like peptide, adiponectin,insulin-like growth factor, and prolactin. The effects of these factors on drug-seeking and drug-taking should next be investigated.